Organ transplantation has emerged as a preferred method of treatment for many forms of life-threatening diseases that involve organ damage. Improved results in clinical transplantation have been achieved primarily through the development of increasingly potent non-specific immunosuppressive drugs to inhibit rejection responses (Lancet, 345:1321-1325 (1995)). While short-term results have improved, long-term outcomes remain inadequate. Currently, life-long immunosuppressive agents are required to combat chronic rejection of the transplanted organ, and the use of these agents dramatically increases the risks of cardiovascular disease, infections and malignancies.
The development of strategies to promote the acceptance of allogeneic tissues without the need for chronic immunosuppression may reduce the risk of these life-threatening complications, and greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies, genetic immunodeficiencies, and autoimmune diseases.
Insulin-dependent diabetes mellitus (IDDM) is one of the most commonly occurring metabolic disorders in the world. In the United States, IDDM affects approximately one in 300 to 400 people, and epidemiological studies suggest that the incidence of IDDM is continuing to increase. IDDM is caused by an autoimmune response that results in the T lymphocyte-mediated destruction of the insulin-producing islet cells of the pancreas.
Once the clinical symptoms of IDDM become evident, the most commonly employed therapy for controlling the clinical symptoms of IDDM is exogenous insulin replacement. Although insulin replacement therapy allows most IDDM patients to lead somewhat normal lives, it does not completely restore metabolic homeostasis, and as a result; severe complications including dysfunctions of the eye, kidney, heart, and other organs are common in diabetic patients undergoing insulin replacement therapy.
A long-sought treatment for IDDM patients is islet transplantation. However, transplanted insulin-producing islet cells are often rapidly destroyed by the same autoimmune response that previously destroyed the patients own islet cells. Of the 260 allografts transplanted since 1990, only 12.4% have resulted in insulin independence for periods of more than one week, and only 8.25% have been insulin independent for periods of more than one year (Linsley et al. Diabetes (1997) 46: 1120-3). In the majority of these procedures, the base regimen of immunosuppression consisted of antibody induction with an anti-lymphocyte globulin combined with cyclosporin, azathiprine, and glucocorticoids.
For any type of transplantation procedure, a balance between efficacy and toxicity is a key factor for its clinical acceptance. With respect to islet transplantation, a further concern is that many of the current immunosuppressive agents with particular glucocortecoids or a calcineurin inhibitor, such as Tarcolimus, damage beta cells or induce peripheral insulin resistance (Zeng et al. Surgery (1993) 113: 98-102).
A steroid-free immunosuppressive protocol (“Edmonton protocol”) that includes sirolimus, low dose Tarcolimus, and a monoclonal antibody (mAb) against IL-2 receptor has been used in a trial of islet transplantation alone for patients with type-1 diabetes (Shapiro, A. M. J. et al, (2000), N. Eng. J. Med., 343: 230-238).
The recent success using the “Edmonton protocol” has renewed enthusiasm for the use of islet transplantation to treat diabetes. However, concerns regarding toxicity of the Tarcolimus may limit the application of this therapy in humans. Biological agents that block key T cell costimulatory signals, in particular the CD28 pathway, are potential alternatives to protect allogeneic islets. Examples of agents that block the CD28 pathway include but are not limited to soluble CTLA4 including mutant CTLA4 molecules.